tbuckley/cabot-search huggingface dataset:
EXTH-11. ADOPTIVE CELLULAR THERAPY OVERCOMES GLIOMA IMMUNE ESCAPE BY DISRUPTING MDSC PROLIFERATION AND RECRUITMENT
Authors: John Figg, Connor Francis, Dan Jin, Bayli DiVita Dean, Laura Falceto Font, Alexandra Reid, Brianna McDonald, David Hilferty, Kaytora Long-James, Catherine Flores
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Our group has previously shown that adoptive cellular therapy (ACT) significantly extends survival in models of medulloblastoma, brain stem glioma, and glioblastoma. Further, ACT significantly decreases myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME), suggesting that ACT may ameliorate glioma-mediated immunosuppression. We hypothesize that ACT-mediated reduction of MDSCs is driven by cell proliferation and recruitment mechanisms, but these mechanisms have not been defined. In this study, we quantified the proportions and cell cycle states of MDSCs in the TME and peripheral lymphoid tissues as well as chemokines in serum to determine how ACT affects MDSC recruitment. METHODS ACT was performed in C57BL/6J mice bearing a syngeneic high-grade glioma derived from KR158B-luciferase cell line. The treatment platform included total body irradiation, hematopoietic stem cell rescue, total tumor ribonucleic acid (ttRNA) electroporated dendritic cells, and tumor-reactive T cells. Following ACT completion, we evaluated the proportions and cell cycle states of MDSCs using flow cytometry. Bromodeoxyuridine (BRDU) and 7-aminoactinomycin (7-AAD) defined cell cycle phases. Serum chemokines were measured using a membrane-based sandwich immunoassay. RESULTS We replicated our previous findings that ACT reduces the level of MDSCs in the TME. Additionally, ACT significantly decreased the proportion of MDSCs in S-phase in the TME. Conversely, levels of MDSCs in peripheral lymphoid tissue were significantly increased in mice treated with ACT, with a significant increase of MDSCs in S-phase. Analysis of serum chemokines revealed significant decreases in multiple chemokines implicated in MDSC recruitment such as CXCL13 and CXCL16. CONCLUSION These findings suggest that ACT decreases proliferation and chemotactic recruitment of MDSCs to the TME, which may also explain MDSC accumulation peripheral lymphoid tissue in ACT-treated mice. These immune mechanisms likely contribute to ACT’s efficacy against brain cancer, preventing tumor immune escape, and offer new therapeutic targets for optimizing cellular immunotherapies.
DNAR-03. A ROLE FOR THE INTERACTION BETWEEN DNA-DEPENDENT PROTEIN KINASE (DNA-PK) AND TAZ IN INDUCING GLIOMA STEM-LIKE CELL (GSC) RADIO-RESISTANCE
Authors: Tiffany Tang, Hiroshi Katayama, Krishna Bhat
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a primary brain tumor that is virtually incurable. Previous studies have shown that glioma stem-like cells (GSCs) are a particularly resistant subpopulation of GBM. Thus, a greater understanding of the mechanisms underlying therapy resistance in GSCs is required. TAZ is a transcriptional cofactor highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. Our group has shown that GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. However, the molecular mechanisms of TAZ-mediated cell fate transition and GBM treatment resistance remain elusive. Previously, our group identified a novel interaction between DNA-dependent protein kinase (DNA-PK) and TAZ in response to exposure to ionizing radiation (IR) in GSCs. Here, we extend our previous findings by contextualizing the significance of this novel interaction in altering sensitivity to IR in GSCs. We demonstrate that prolonged culture of GSCs treated with etoposide increases TAZ expression. Furthermore, si-RNA knockdown of TAZ increases the number of γH2AX foci post-IR. Intriguingly, knocking down both TAZ/YAP does not increase the number of γH2AX foci post-IR in comparison to single knockdown of TAZ. Additionally, DNA-PK inhibitor treatment in GSCs reduces the half-life of TAZ. In contrast, GSCs treated with IR increases the half-life of TAZ compared to mock-irradiated cells. A combination of IR and DNA-PK inhibitor treatment in GSCs reduces the half-life of TAZ compared to GSCs treated with IR and DMSO, implicating the role of the recruitment of TAZ to DNA damage breaks and its resulting interactions with DNA-PK to induce radio-resistance. Overall, this study reports how interaction of DNA-PK with TAZ globally induces a GSC radio-resistant phenotype, highlighting the potential role of TAZ as a therapeutic target for GBM.
CTNI-23. SINGLE CELL TRANSCRIPTOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF COMBINED CDK4/6 AND MTOR INHIBITION IN A PHASE 0 TRIAL OF RECURRENT HIGH-GRADE GLIOMA
Authors: Kevin Johnson, An-Chi Tien, Jun Jiang, James McNamara, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Leonel Elena, Yoko Fujita, Seongho Kim, Artak Tovmasyan, Jing Li, Shwetal Mehta, Roel Verhaak, Nader Sanai
Journal: Neuro-Oncology (2023)

Abstract Adult High-grade gliomas (HGGs) often exhibit deregulation of RB-CDK4/6 and mTOR signaling pathways. This study investigated tumor single cell transcriptomics, pharmacokinetics, and pharmacodynamics immediately following combined CDK4/6 (ribociclib) and mTOR (everolimus) inhibition in recurrent HGG. 24 patients with recurrent gliomas harboring RB+, CDKN2A/B deletion or CDK4/6 amplification, and PTEN loss or PIK3CA mutations were enrolled in a phase 0 trial. Patients received ribociclib treatment for 5 days before surgery, including six who received ribociclib (400mg QD) plus everolimus (2.5mg QD), and six dose-escalation cohorts (n = 3 each) reaching ribociclib 600mg QD plus everolimus 70mg QW. No dose-limiting toxicities were observed. Validated LC-MS/MS methods determined total and unbound drug concentrations. Preoperative MRI revealed a marked decrease in gadolinium-enhancement in all patients. In gadolinium-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM, while no unbound everolimus concentrations were detected. Ribociclib’s pharmacodynamic effects in surgical specimens were compared with matched archival tissue using IHC. Across IDH-wild-type tumors, there was significant decrease in MIB1 levels between the matched archival and surgical specimens (p &amp;lt; 0.05) suggesting drug-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) analyses were performed on 17 IDH-wild-type recurrent samples treated with ribociclib plus everolimus and 29 IDH-wild-type recurrences treated with standard therapies. Cellular state analysis based on snRNAseq data demonstrated a decreased neural progenitor-like (NPC-like) malignant cell state compared with standard therapies (p &amp;lt; 0.01), indicating inhibition of the CDK4-driven neural progenitor-like cell state. This observation was validated using snRNA and patient-derived glioma cell lines exposed to ribociclib, showing a consistent decrease in NPC-like proportions and cycling cells (p &amp;lt; 0.05). This study highlights the value of integrating pharmacokinetics/pharmacodynamics and snRNA data to assess treatment effects in phase 0 surgical tissues. These findings support further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTNI-73. ALLIANCE A071601: PHASE II TRIAL OF BRAF/MEK INHIBITION IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS
Authors: Priscilla Brastianos, Erin Twohy, Susan Geyer, Elizabeth Gerstner, Timothy Kaufmann, Shervin Tabrizi, Brian Kabat, Julia Thierauf, Michael Ruff, Daniela Bota, David Reardon, Adam Cohen, Macarena de la Fuente, Glenn Lesser, Jian Campian, P K Agarwalla, Priya Kumthekar, Bhupinder Mann, Shivangi Vora, Michael Knopp, A John Iafrate, William Curry, Daniel Cahill, Helen Shih, Paul Brown, Sandro Santagata, Frederick Barker, Evanthia Galanis
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.
BIOM-33. TRNA FRAGMENTS IN PLASMA EXTRACELLULAR VESICLES FROM HIGH GRADE GLIOMA PATIENTS, POTENTIAL BIOMARKERS?
Authors: Adrienne Weeks, Thomson Phinney, Ali Alwadei, Gabriel Wajnberg, Jae Han, Simi Chacko, Kathleen Atwood, Jeremy Roy
Journal: Neuro-Oncology (2023)

Abstract Transfer RNA (tRNA) are non-coding RNAs responsible for bringing the amino acids to the ribosome during translation. Recent studies in cancer have shown that fragments (tRFs) derived from tRNA cleavage serve regulatory roles in epigenetics, signalling and translation. tRFs are also released from cells bound to proteins and can be found in extracellular vesicles to perform some aspects of paracrine signalling. Utilizing high throughput small RNA sequencing we have identified over 750 uniquely or multi-mapped (6.9% of total sRNA mapped reads) tRNA and tRFs in extracellular vesicles of high-grade glioma patient plasma (IDH-WT). Consistent with novel literature in other cancers there was a general trend to decreased expression of tRNA and tRFs (n = 76 with FDR &amp;lt; 0.05) in high grade glioma plasma EVs compared to controls. However, further analysis of tRFs reveals a much more complex story, as fragment distribution differs between cancer and controls. tRNAs and tRFs may serve as important biomarkers and regulators with therapeutic potential in the future.
CTNI-78. EVALUATION OF POST-PROGRESSION TREATMENTS AFTER VAL-083 IN RECURRENT AND NEWLY DIAGNOSED GBM MGMT-UNMETHYLATED PATIENTS
Authors: Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, W K Alfred Yung, Monica Loghin, Nazanin Majd, Dennis Brown, John Langlands, Richard Schwartz, Stephanie Knight, Vinay Puduvalli, John de Groot, Barbara O'Brien
Journal: Neuro-Oncology (2023)

Abstract Almost all GBM patients experience recurrent disease following up-front standard of care treatment, with a median survival of 3-9 months after recurrence. Challenges with salvage therapies include the potential for side-effects, which may limit further treatment. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death independently of MGMT DNA repair and DNA mismatch repair deficiency. VAL-083 was evaluated in an open-label two-arm biomarker-driven phase 2 trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with TMZ (Group 2). Post-progression, patients were followed for survival status, and any post-VAL-083 treatments. Here we review treatments received by patients following participation in this clinical trial, and their outcomes. Patients were excluded from the review if no data had been collected or if they had undergone subsequent surgery. Group 1(n=42) and Group 2(n=31) who received 30 mg/m2 VAL-083 (days 1-3 of 21-day cycle) were evaluated. In Group 1 and Group 2, 17/42 (40.5%) and 20/31 (64.5%), respectively, received an alkylating agent post-VAL-083. Receiving more than the median number of cycles of VAL-083 in either group didn’t limit patients from receiving alkylating agents such as CCNU and TMZ after VAL-083. No hematologic complications were identified. Furthermore, receiving ≥5 cycles of adjuvant TMZ prior to VAL-083 in Group 1 didn’t affect patient’s ability to receive alkylating agents. For both groups, mOS and OS-6 from the last dose of VAL-083 were greater for those receiving alkylating agent post VAL-083, compared to those who didn’t. These data demonstrate that alkylating agents may be administered safely to patients who have progressed following therapy with VAL-083, and patients who have received an alkylating agent after VAL-083 therapy have a better outcome compared to those receiving other treatments.
DISP-09. HISTOPATHOLOGIC AND MOLECULAR PROFILE OF GLIOMAS: A 9-YEAR RETROSPECTIVE STUDY OF CASES DIAGNOSED IN LAGOS NIGERIA
Authors: Lateef Odukoya, Thomas Kollmeyer, Jeanette Eckel-Passow, Cristine Ida, Daniel Lachance, Ekokobe Fonkem, Kabir Badmos, Olufemi Bankole, Gaspar Kitange, Adetola Daramola, Charles Anunobi, Robert Jenkins
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the 2021 WHO classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA); after manual macrodissection for tumor enrichment using 10μm sections. IHC for IDH1-R132H, ATRX, BRAFV600E, P53,Ki67, and H3K27M and OncoScan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of 56 cases evaluated, median age was 22 years (range=1-60 years); 71% were males. The initial morphologic diagnosis include 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥ 750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised 2021 WHO diagnosis were: 5 glioblastoma, IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXAs, 3 astrocytoma, IDH-mutant, 2 pediatric low-grade glioma, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases, diagnosis was revised using the 2021 WHO criteria. CONCLUSION Most cases had usable DNA yield. Overall, hsitologic re-evaluation and molecular testing based on the 2021 WHO classification guidelines refined the diagnosis in 48% (27/56) of cases.
EPCO-52. SUBTYPES AND SURVIVAL ANALYSIS OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA WITH RADIOMICS FEATURES
Authors: Noemie Barillot, Agusti Alentorn, Isaias Hernandez, Karima Mokhtari, Khe Hoang-Xuan, Bertrand Mathon
Journal: Neuro-Oncology (2023)

Abstract Primary Central Nervous System Lymphoma (PCNSL) is a rare and heterogeneous disease with dismal prognosis. Recently, four molecular clusters with clinical relevance have been identified with different potential therapeutic targets in each group. Nevertheless, multi-omics data collection and analysis are expensive and not adapted for clinical practice. Therefore, the identification of surrogate markers to identify PCNSL subtypes from routine data is required, like using hematoxylin and eosin slides from brain biopsies. We used a cohort of 108 patients and we selected the 5000 nuclei for each patient among roughly 1,500,000 nuclei. Once hematoxylin and eosin slides have been digitized, tessellated, normalized and the nuclei have been segmented and filtered with the computation of a solidity score, the PyRadiomics package provides us with more than 800 features for each nuclei. Firstly, we were interested in survival analysis. In a second time, we also used these features for training classification models. We used a partial least squared Cox model, which is a classic Cox model applied to latent components constructed by using linear combinations of the original variables. RESULTS: for our first cohort are promising (C-index of 0.87, std 0.01), with a significant increase compared to the clinical features model (C-index of 0.68, std 0.03). We are now challenging these results with three other cohorts of brain and systemic lymphoma. This study paves the way for a stratification of the clinical evolution based on the machine learning analysis of digital pathology in PCNSL that could be easily translated to a broad range of diseases or other brain tumors.
IMMU-34. SYSTEMIC IMMUNE SUPPRESSION IN GLIOBLASTOMA IS TARGETED BY CONCURRENT VEGF AND PD-1 INHIBITION IN A DOSE-DEPENDENT MANNER: TRANSCRIPTOMIC FINDINGS THROUGH CITE-SEQ FROM A RANDOMIZED CONTROLLED TRIAL
Authors: Ahmad Ozair, Tyler Alban, Matthew Grabowski, Balint Otvos, Defne Bayik, Anas Bamashmos, Pat Rayman, Marcella Diaz, Atulya Khosla, Shreyas Bellur, Michael McDermott, David Reardon, Patrick Wen, Alireza Mohammadi, David Peereboom, Justin Lathia, Manmeet Ahluwalia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Anti-PD1 blockade has had poor efficacy in recurrent glioblastoma (rGBM) across three RCTs. VEGF, a proangiogenic factor that is upregulated in rGBM, contributes to tumor-associated immunosuppression and is widely targeted through bevacizumab. Preclinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD-1 and anti-VEGF agents is a promising approach for rGBM, for which an RCT was conducted. This work sought to utilize a multimodal approach capturing single-cell gene and protein expression by ‘cellular indexing of transcriptomes and epitopes by sequencing’ (CITE-Seq) to interrogate the systemic immunological changes in response to concurrent VEG and PD-1 inhibition. METHODS Patients with rGBM were administered nivolumab (240mg IV q2weeks) plus either standard-dose bevacizumab (10mg/kg) or low-dose bevacizumab (3mg/kg) IV q2weeks, with 1:1 randomization. Stratification factors were age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months. CITE-Seq was performed on 16 patients across trial arms, both pre- and on-therapy, yielding total 32 immunological profiles. For control, CITE-seq was done on three patients receiving anti-VEGF therapy alone. RESULTS 90 patients were enrolled with median age of 60.6 years and 45 patients per arm. Both arms had similar OS at 12 months (P=0.14). Significantly higher OS was found in posthoc analysis for patients aged ≥60 years with standard dose. Distinct immune cell populations were identified, and differential changes in myeloid-derived suppressor cells (MDSCs) found across trial arms on-therapy. Network medicine approach identified VEGF as target to reduce MDSCs, with VEGF primarily expressed by responders’ MDSCs. Differential gene expression analysis identified increased pro-inflammatory signatures in standard-dose arm. CONCLUSIONS Standard dose bevacizumab was associated with increased inflammatory response and reduction of immunosuppressive MDSC. These mechanistic insights potentially explain survival benefit seen with concurrent VEGF and PD-1 inhibition in elderly rGBM patients.
INNV-08. LONG-TERM GLOBAL POST-MARKETING SAFETY SURVEILLANCE DATA FROM PEDIATRIC, ADULT AND ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Maciej Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas Lukas, Joshua Palmer, John Suh, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety data from pediatric, adult and elderly patients with CNS malignancies receiving TTFields, from a global post-marketing surveillance (PMS) dataset. METHODS Unsolicited PMS data were collected from patients receiving TTFields (October 2011–October 2022). AEs were categorized using MedDRA version 25.1, and data stratified by age group (&amp;lt; 18, 18–65, and &amp;gt; 65 years). RESULTS Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were &amp;lt; 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were &amp;gt; 65 years (elderly). Two-thirds (66%) of all patients were male. Demographic characteristics were therefore consistent with a typical GBM population. Of pediatric patients, 62% experienced ≥ 1 AE, with 53% related to TTFields. This was comparable in adults (72% and 56%, respectively), and elderly patients (75% and 57%, respectively). The most common TTFields-related AEs were skin reaction (pediatric: 39%; adult: 42%; elderly: 45%), heat (warmth) sensation (pediatric: 14%; adult: 12%; elderly: 12%), and electric (tingling) sensation (pediatric: 10%; adult: 15%; elderly: 10%). All-cause serious AEs occurred in 14%, 21% and 25% of pediatric, adult and elderly patients, respectively. No systemic toxicities were reported, regardless of age. CONCLUSIONS These long-term, real-world PMS data demonstrate that TTFields has a tolerable safety profile in pediatric, adult and elderly patients with CNS malignancies, with no new safety signals in any age group. Most AEs were localized skin reactions which are manageable. These data provide supportive evidence of the safety and broad applicability of TTFields, regardless of patient age.